The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development. Muscle spindles are sensory receptors embedded within muscle that detect changes in muscle length. Each spindle is composed of specialized muscle fibers, known as intrafusal muscle fibers, and the endings of axons from sensory neurons that innervate these muscle fibers and that convey length information to the CNS. Formation of muscle spindles is regulated by inductive interactions between muscle fibers that ultimately will become intrafusal fibers and sensory axons that contact them. A critical part of this inductive process is neuregulin (NRG) 1, a secreted signaling protein, being released by sensory axons, and in turn activating its receptors, ErbB proteins, in muscle cells that are contacted. The proposed research focuses on the intracellular pathway activated by ErbBs, which is critical for muscle spindle formation but for the most part has not been determined. Despite the uncertainty about how the intracellular response occurs, one critical component that has been identified is the transcription factor Egr3, which is transcriptionally induced as part of NRG-ErbB signaling and in turn activates various target genes involved in formation of muscle spindles. The proposed research focuses on the signaling relay that acts upstream of Egr3 by identifying transcriptional regulatory proteins that are required for inducing transcription of Egr3 in response to NRG1 and determining how these transcriptional regulatory proteins are acted upon by the NRG1-ErbB pathway. In addition to providing insight into muscle spindle formation, results obtained from this research might also be applicable to how NRG1- ErbB signaling regulates gene expression in other cell types in which it functions, to how Egr3, which functions as part of a variety of signaling pathways, is regulated within these pathways, and to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Because certain sensory neuropathies involve destruction of nerves and their connections, understanding the signaling interactions that control formation of mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies. PUBLIC HEALTH RELEVANCE: The proposed research addresses how sensory neuron innervation of muscle regulates gene expression during muscle spindle development and may also be applicable to formation of other mechanosensory structures that are induced by the sensory axons that innervate them. Certain sensory neuropathies involve destruction of nerves and their connections. Understanding the signaling interactions that control formation of muscle spindles and other mechanosensory structures might suggest regenerative approaches for treating certain sensory neuropathies.